The central objective of the proposed research is to launch a new era of molecular genetics in a large national study of American adults, known as MIDUS (Midlife in the U.S.). Begun in 1995, MIDUS has become a major forum for multidisciplinary research on aging from early adulthood through later life, with a huge following from the scientific community (most frequently downloaded dataset at the national Archive of Computerized Data on Aging). Scientific productive from the study is extensive (about 400 publications), key themes of which clarify that the primary competitive advantage of MIDUS for molecular genetics is its comprehensive and cumulative assessments of environmental exposures. We will focus on two key exposures, socioeconomic status (SES) and social relationships (SR), which constitute well established influences on morbidity and mortality from social epidemiology. We build our specific aims around an explicit gene by environment approach to three outcomes: emotional distress, cognition, and inflammation. In each (Aims 1 through 3), we target primary genetic markers (i.e., those receiving the lion's share of attention in prior research as well as those for which there are functional rationales with regard to underlying neurobiological mechanisms) and examine the role of SES and SR environmental exposures as moderators of their influence on outcomes. Incorporating both risk and protective moderators, we will focus on cumulative SES disadvantage and cumulative SR advantage. An additional set of provisional genetic markers will also be included as supplemental analyses. The proposed work will be carried out with members of the MIDUS Refresher sample (newly recruited respondents) and the existing longitudinal sample (projected sample size for testing key gene by environment hypotheses is 5,400 adults). Embedded within MIDUS is also a national sample of twins for which additional gene by environment analyses will be conducted as well as analyses guided by a co-twin control design. A final aim of the proposed research is to create a genetic repository from the saliva-based DNA extraction and to then hold workshops in the final two years of the grant drawing on scientists from around the country to discuss plans to optimally leverage the use of this repository in a national study with unprecedented depth in assessment of diverse environmental exposures, only two of which are investigated in the proposed research. Overall, the future scientific inquiry that will emanate from the proposed plans to bring molecular genetics to MIDUS is of exceptional scope.